Synthesis and Biological Evaluation of 2‐Substituted‐5‐(4‐nitrophenylsulfonamido)benzoxazoles as Human GST P1‐1 Inhibitors, and Description of the Binding Site Features

Abstract

Glutathione-S-transferases (GSTs) are enzymes involved in cellular detoxification by catalyzing the nucleophilic attack of glutathione (GSH) on the electrophilic center of numerous of toxic compounds and xenobiotics, including chemotherapeutic drugs. Human GST P1-1, which is known as the most prevalent isoform of the mammalian cytosolic GSTs, is overexpressed in many cancers and contributes to multidrug resistance by directly conjugating to chemotherapeutics. It is suggested that this resistance is related to the high expression of GST P1-1 in cancers, thereby contributing to resistance to chemotherapy. In addition, GSTs exhibit sulfonamidase activity, thereby catalyzing the GSH-mediated hydrolysis of sulfonamide bonds. Such reactions are of interest as potential tumor-directed prodrug activation strategies. Herein we report the design and synthesis of some novel sulfonamide-containing benzoxazoles, which are able to inhibit human GST P1-1. Among the tested compounds, 2-(4-chlorobenzyl)-5-(4-nitrophenylsulfonamido)benzoxazole (5 f) was found as the most active hGST P1-1 inhibitor, with an IC50 value of 10.2 μM, showing potency similar to that of the reference drug ethacrynic acid. Molecular docking studies performed with CDocker revealed that the newly synthesized 2-substituted-5-(4-nitrophenylsulfonamido)benzoxazoles act as catalytic inhibitors of hGST P1-1 by binding to the H-site and generating conjugates with GSH to form S-(4-nitrophenyl)GSH (GS-BN complex) via nucleophilic aromatic substitution reaction. The 4-nitrobenzenesulfonamido moiety at position 5 of the benzoxazole ring is essential for binding to the H-site and for the formation of the GST-mediated GSH conjugate.

Synthesis and structure–activity relationship of new cytotoxic agents targeting human glutathione-S-transferases

“…Instead, the introduction of the carboxy function in ortho (6) or meta (7), or an N-hydroxy- (11) carboxamido group at the para position of the C4-phenylthio moiety increases the water solubility at approximately 1e2 mM (Table 1). Also the insertion, at the C4-sulfur atom, of a 2-acetamidoethyl (26) or N-hydroxyethyl-propanamide (27) or 4-piperidonyl-1-ethyl (28) side chain results in improved water solubility (1 mM) of the derivatives, as well as the decrease of the methylene units of 1 from 6 to 4 (35).…”

Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists

“…In this study, to describe the antagonist activity of some compounds which were previously synthesized by our team comparing with the standart drug aprepitant [18,35,36], MTT assay was applied (Table 1). Among these compounds BADA-034, BSN-009, BON-254, BADA-024 were tested for their cytotoxic activities in MCF-7, HeLa and HT-29 cancer cell lines, and NIH3T3 mouse embryonic fibroblast cell line.…”

“…In this research, NK1R antagonist activity of some previously synthesized compounds [18,35,36] MTT assay was applied. BSN-009 was found to be the most active compound among the others, and also inhibited colon cancer cell lines growth, comparing to the standard drug aprepitant.…”

“…Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20]. These findings encouraged us to search for the new anticancer target NK1R by comparing their activities with the well-known NK1R antagonist aprepitant.…”

“…Over the last decade our group have been working on the drug design studies on the new anticancer active compounds by using both computational techniques and experimental work such as synthesis and activity studies [12][13][14][15][16][17][18][19][20]. Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20].…”